The present invention relates to novel neutral mixed ligand platinum(II) and platinum(IV) complexes useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to a pharmaceutical method of treatment. More particularly, the novel complexes of the present invention are active against the L1210 and P388 murine leukemia cell lines, thus inhibiting the growth of malignant neoplasms in mammals.
Various platinum compounds have been shown to possess antitumor activity. This has been highlighted by the clinical utility of cisplatin (A) ##STR1## in the treatment of human tumors. However, because of the severe toxicity, especially nephrotoxicity, associated with the therapeutic use of cisplatin, a number of additional platinum(II) and platinum(IV) analogs have been synthesized and evaluated for antitumor activity. Thus, U.S. Pat. No. 4,169,846 discloses platinum(II) complexes which exhibit antitumor activity in mice of formula ##STR2## wherein the stereoisomerism of 1,2-diaminocyclohexane is cis-, trans-d-, or trans-l; and R.sup.1 and R.sup.2 represent the same halogen atoms, or R.sup.1 and R.sup.2 may, when taken together, form a group represented by the formula ##STR3## where R.sup.3 represents a &gt;CH.sub.2 group, a &gt;CHCH.sub.3 or &gt;CHCH.sub.2 CH.sub.3 group. Further, it relates to complexes of uracil and cis[platinum(II)-cis, trans-d-, or trans-l-1,2-diaminocyclohexane].
European Patent Application 0098121 discloses platinum(II) complexes which exhibit antitumor activity in mice of formula ##STR4## wherein X is a halogen atom and G is a glucuronic acid residue.
Witiak, D. T., et al., Journal of Medicinal Chemistry, 30, pages 1327-1336 (1987) reported the synthesis and antitumor evaluation of a series of diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexane platinum(II) complexes.
European Patent Application 0237450 discloses platinum(IV) complexes which exhibit antineoplastic or antitumor activity of formula ##STR5## wherein the moiety ##STR6## denotes a 1,2-cyclohexanediamine ligand of the formula: ##STR7## where the 1- and 2-amino groups show a configuration selected from cis-, trans-l- and trans-d- relative to the cyclohexane ring, or the moiety ##STR8## denotes a (aminomethyl)cyclohexylamine ligand of the formula where the 1-amino group and 2-aminomethyl group show a configuration selected from cis-l-, cis-d-, trans-l- and trans-d-, or a mixture thereof relative to the cyclohexane ring; B and B' taken together with the platinum atom form a ring of the formula ##STR9## Japanese Patent Application 63-17,894 discloses a series of cis-diaminocyclohexanolplatinum complexes represented by any of the general formulas: wherein R.sup.1 -R.sup.8 stand for a hydrogen atom or a hydroxyl group. These hydroxyl-containing diaminocyclohexane derivative were disclosed as exhibiting antitumor activity.
However, the previous complexes of platinum(II) and platinum(IV) suffer the drawbacks of inadequate water solubility and/or an unacceptable therapeutic index. Additionally, in the previous known platinum complexes of 1,2-diaminocyclohexane (DACH) the cyclohexane ring can assume a normal chair configuration. In contrast, the compounds of the present invention, in particular the 1,4-diaminocyclohexane (DACH) derivatives, are structurally unique in that the cyclohexane ring is constrained to a boat configuration. This appears to be the first example of this type of structural novelty in coordination chemistry. Thus, we have found unexpectedly that the platinum(II) and platinum(IV) complexes of the present invention have increased water solubility and antineoplastic activity over the compounds of the prior art.